Recent studies have shown that myelodysplastic syndrome’s (MDS) progression to acute myeloid leukemia (AML) is associated with gene mutations. SET domain containing 2 (
SETD2
) variants were reported as a risk factor of poor prognosis in patients with AML. However, little is known about the potential contribution of the
SETD2
gene in MDS. In this study, we investigated the roles of
SETD2
gene mutations/variants on clinical features and prognosis in patients with MDS. A 43-gene panel was used for next-generation sequencing in 203 patients with primary MDS, and then the effects of
SETD2
mutation on Wnt/β-catenin signaling was investigated during the different stages of MDS. At a median follow up of 33 months, 65 (32.0%) deaths and 94 (46.3%) leukemic transformations were recorded. The most frequent mutations/variants included
TET2
,
DNMT3A
, and
ASXL1
mutations/variants. 37 patients had
SETD2
gene mutations/variants, and these patients exhibited a significantly increased frequency of
TP53
mutations. Multivariate survival analyses indicated that
SETD2
mutations/variants were closely associated with overall survival (OS), and they were identified as risk factors for progression-free survival (PFS), especially with low expression of
SETD2
gene. Further, we found that
SETD2
loss could promote MDS progression via upregulation
DVL3
mRNA level in BM cells and it could also cause genomic instability. Secondary mutations, such as
TP53
and
FLT3
mutations, were acquired at the time of progression to AML. In conclusion, we showed that
SETD2
deficiency was associated with poor outcomes in patients with MDS. Moreover,
SETD2
deficiency may upregulate
DVL3
expression and modulate genomic stability that caused AML transformation.
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